STRUCTURAL DATA ANALYSIS a. Subcortical Volume in alcohol dependence The effect of polysubstance use Chronic alcohol use has widespread effects on brain morphometry. Alcohol dependent individuals are often diagnosed with comorbid substance use disorders. Alterations in brain morphometry may be different in individuals that are dependent on alcohol alone and in individuals dependent on alcohol and other substances (polysubstance users). We examined subcortical brain volumes in individuals with alcohol dependence only (ADO), individuals with polysubstance use disorder (PS) and 37 healthy control participants (HC). Participants underwent a structural MR scan and a model-based segmentation tool was used to measure the volume of 14 subcortical regions. Compared to HC, ADO had smaller volume in the bilateral hippocampus, right nucleus accumbens and right thalamus. PS only had volume reductions in the bilateral thalamus compared to HC. PS had a larger right caudate compared to ADO. Subcortical volume was negatively associated with drinking measures only in the ADO group. This study confirms the association between alcohol dependence and reductions in subcortical brain volume. It also suggests that polysubstance use interacts with alcohol use to produce limited subcortical volume reduction and at least one region of subcortical volume increase. These findings indicate that additional substance use may mask damage through inflammation or may function in a protective manner, shielding subcortical regions from alcohol-induced damage (Grodin and Momenan, 2016). b. Impulsivity, Compulsivity, and Insula Volume in Alcohol Dependence We have previously shown that alcohol dependence is associated with decreased insula volume (Senatorov et al., 2015). Recently, preclinical studies have identified the anterior insula as a potential substrate for impulsivity and compulsivity (Belin-Rauscent et al, 2016). Individuals with alcohol addiction have increased scores on self-report measures of impulsivity as well as behavioral measures of impulsivity. Moreover, compulsivity, the tendency to repeat a previously rewarded behavior despite the removal of reward or in the face of aversive consequences, is a hallmark of addiction. In rats, lesions of the anterior insula resulted in decreased levels of behavioral impulsivity and decreases in compulsive water drinking behavior (Belin-Rauscent et al, 2016). We sought to investigate the relationship between insula morphometry, impulsivity, and compulsivity in individuals with varying levels of alcohol problems. Light drinkers, problem drinkers with no alcohol use disorder diagnosis, non-treatment seeking individuals with an alcohol use disorder diagnosis, and treatment seeking individuals with an alcohol use diagnosis underwent a structural MR scan and self-report impulsivity and compulsivity measures were obtained. Freesurfer software was used to parcellate the brain. There were group differences in all impulsivity and compulsivity measures, with treatment-seeking individuals having the highest scores and light drinkers having the lowest scores. There were significant group differences in bilateral anterior insula volume and surface, but no differences in cortical thickness. Furthermore, impulsivity and compulsivity mediated the relationship between left anterior insula volume and AUDIT scores, a measure of alcohol use problems. These results indicate that the anterior insula is a potential substrate for the maladaptive behaviors associated with increased impulsivity and compulsivity associated with alcohol addiction (manuscript in preparation). EXTRAMURAL COLLABORATIONS 1. Cerebellar recovery of alcohol dependent patients during short term abstinence We are conducting collaboration with Dr. George Fein of Neurobehavioral Research, Inc. (NRI) in a funded U01 grant to develop and apply a 30 parcel active appearance model of the cerebellum on prospective motion tracking and corrected structural MRIs. CNIRC plays a key role in identifying appropriate subjects from ongoing studies in order to maximize the clinical, behavioral, and neuropsychological data available for analysis. A total of 18 subjects have been acquired and made available for modeling since March. Each subject comprises 4 first-visit scans: 1 mm3 T1 motion-corrected, 1 mm3 T1 standard, and two 0.7 mm3 T1 motion-corrected images with re-entry. Sixteen of these subjects have second-visit scans comprising: 1 mm3 T1 motion-corrected, 1mm3 T1 standard, and one 0.7 mm3 T1 motion-corrected images. Thirteen 0.7 mm3 scans have minor ghosting artifacts that are not prevalent in the region of the cerebellum and should not pose a problem. Statistical models of shape and intensity will be trained from expert manual delineations of a subset of the acquired images. Development of the extended 30-parcel manual labeling protocol is being undertaken in three stages by Neuromorphometrics Inc. Stage 1 comprised an initial set of 5 T1 images (from Kineticor system), and was completed in June. These images have been analyzed and used to develop CATK-2 appearance models. Stage 2 is now underway using 20 images from the latest NIAAA provided data, taken from first- and second-visits of 10 subjects (0.7mm3 T1 motion corrected). 2. Addiction ENIGMA Jointly, with our counterparts at the National Institute on Drug Abuses Neuroimaging Research Branch of Dr. Elliot Stein, we initiated the NIH Addiction Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA). This initiative is part of the Addiction-ENIGMA consortium, a large, multi-site, data-pooling initiative focused on genetics and the brain that has analyzed tens of thousands of study participants at more than 100 labs in over 30 countries. We have already contributed to a number of conference presentations and one review publication (Mackey et al, 2016) using volumetric data from structural images. We have recently completed our contribution to another study utilizing diffusion tensor imaging. OMNIBUS ALCOHOL NEUROIMAGING ASSESSMENTS The purpose of this study is to obtain a standard set of assessments, including brain behavioral, structural, functional, and connectivity (structural and functional) information, on all NIAAA research participants, referred to hereinafter as Characterization Imaging Instruments (CII); a) to determine how individual differences in brain structure and evoked responses relate to generalized trait personality and behavior differences (as assessed by psychometric questionnaire instruments and behavioral measures); and b) to determine whether these individual differences relate specifically to genetic polymorphisms in genes governing neurotransmitter activity. Currently we have structural and functional neuroimaging data for over 37 alcohol dependent patients as well as 80 healthy controls. This data are collected from motivational, emotional, and decision making tasks. This in turn might enable us to identify and establish an Addictions Neuroimaging Assessment (ANiA). Create a standardized neuroimaging assessment to provide AD subtyping phenotypes using information from: resting state and task driven functional connectivity; neurocircuitries associated with AD domains; gray and white matter structural integrity of the human brain in various stages of this heterogeneous disease. Develop a big data system that enables the use of ANA and ANiA assessments and phenotypic data. Determine the neural correlates (i.e. networks) associated with the domains and neuroclinical measures of alcohol use disorders. Utilize innovative approaches such as machine learning to assist in individualized patient treatment, treatment efficacy, and relapse prediction.